According to the National Cancer Institute, approximately 4,000 specific conditions are known to be caused by genetic detects. The GeneMed Network states that each human being carries roughly a half dozen defective genes, and that about one in ten people has or will develop an inherited genetic disorder.
A composite of approximately 150,000 individual genes constitutes a human being. Variation in the structure of these genes can lead to disease. Many diseases are hereditively passed by a single gene, while many others are influenced by a collection of genes.
Several years ago, the Human Genome Project began mapping every human gene. The project is fostering an understanding of the very foundation of human disease and is enabling new therapies to treat and predict the onset of disease. One such therapy is gene therapy, which seeks to directly and beneficially modify the expression of genes through delivery of engineered genetic material. Foreign nucleotide sequences of either DNA or RNA are inserted into a patient's cells to result in either expression of non-integrated sequences or integration of sequences directly into the DNA of the cells.
Safe and efficient delivery of nucleotide sequences to appropriate cells poses one of the primary challenges to gene therapy. Vectors, which encapsulate therapeutic genes, have been developed to deliver the sequences. These vectors may be either viral or synthetic. Viral vectors, derived from viruses, are the primary vectors in experimental use today. Viruses efficiently target cells and deliver genome, which normally leads to disease. However, viral vectors for gene therapy are modified so that they may not cause disease. Rather, therapeutic recombinant genes are inserted into the vectors and delivered to target cells. Optimally, the modified viruses retain their ability to efficiently deliver genetic material while being unable to replicate.
Research in the field of gene therapy is still in the formative stages. Human trials only began in 1990 with ex vivo techniques, wherein a patient's cells were harvested and cultivated in a laboratory and incubated with vectors to modify their genes. Cells were then harvested and intramuscularly transplanted back into the patient. Trials quickly shifted to in vivo techniques, in which viral vectors are administered directly to patients, again intramuscularly. A variety of diseases are currently being evaluated as candidates for gene therapy, and a need exists in the art for improved vector delivery techniques.
While significant progress has been made, current gene therapy delivery techniques have many drawbacks. Viral vectors are inherently dangerous due to the innate ability of viruses to transmit disease. Furthermore, long-term effects of using viruses as delivery vehicles are unclear. Chances for error in modifying the viruses to vectors are significant, and consequences may be substantial, including potential irreversible alteration of the human gene pool. Also, delivery of the vectors to an efficacious portion of diseased cells has proven difficult and expensive.
Synthetic vectors have been developed to address the potential for disease transmission with viral vectors. These vectors are complexes of DNA, proteins, or lipids, formed in particles capable of efficiently transferring genes. However, synthetic vectors have thus far proved less effective than viral vectors and have been slower to gain acceptance.
Perhaps even more problematic than limitations of the vectors, intramuscular in vivo techniques, wherein vectors are delivered into a patient's muscle tissue, have proven somewhat ineffective in clinical use. Systemic expression of inserted sequences is not realistic since therapy is localized.
In view of the drawbacks associated with previously known methods for delivery of gene therapy, it would be desirable to provide methods and apparatus that overcome such drawbacks.
In addition to gene therapy techniques, research has focused on the selective implantation or injection of cells or specific proteins to mitigate disease states, cause tissue regeneration or improve organ function. For example, researchers have investigated improvement of cardiac function by injecting cells via epicardial, endocardial or coronary sinus access routes into the myocardium. See, e.g., Thompson, C. A., et al., Percutaneous Transvenous Cellular Cardiomyoplasty, A Novel Nonsurgical Approach for Myocardial Cell Transplantation, J. Am. Coll. Card., 41(11):1964-71 (2003).
Others have investigated injecting cells into the pancreas or liver to improve insulin production in diabetics. Kodama et al., Islet Regeneration During the Reversal of Autoimmune Diabetes in NOD Mice, Science, 302(5648):1223-1227 (2003), describes the injection of donor spleen cells from non-diabetic mice into diabetic mice so that a protein complex secreted by the spleen cells could mitigate the autoimmune disorder causing diabetes. Hering, B. J., et al., Transplantation of cultured islets from two-layer preserved pancreases in type 1 diabetes with anti-CD3 antibody, Am. J. Transplant. 4(3):390-401 (2003), describes infusion of isolated islets of Langerhans into a patient to alleviate Type-I diabetes. Panaro, F., et al., Auto-islet transplantation after pancreatectomy, Expert Opin. Biol. Ther., 3(2):207-14 (2003), describes the infusion of isolated islet cells through a catheter and into a vein in a patient's liver following partial pancreatectomy, so that the islets graft onto and function similarly to the removed liver.
Still others have discovered that certain proteins, such as apolipoprotein A-I Milano, when introduced into the rats fed a high cholesterol diet, inhibits the onset of arterial thrombus formation, as reported in Li, D. et al., Inhibition of arterial thrombus formation by ApoAl Milano, Arterioscler. Thromb. Vasc. Biol., 19:378-83 (1999). Chiesa, G. and Sirtori, C. R., report in Apolipoprotein A-I(Milano): current perspectives, Curr. Opin. Lipidol. 14:159-63 (2003) that recombinant apolipoprotein A-I (Milano), formulated as synthetic HDL with phospholipids, appears to exert a direct removing effect on arterial cholesterol when infused into subjects at different doses.
In view of the foregoing, it further would be desirable to provide methods and apparatus for delivering cells, cell components or naturally-occurring or synthetic proteins into the vascular system of a patient to achieve a treatment goal.
It still further would be desirable to provide methods and apparatus for providing localized delivery of genes, cells or bioactive agents into a patient's vascular system that have a preselected residency beyond that obtainable by systemic or localized intravascular infusions.
It also would be desirable to provide methods and apparatus for delivering viral vectors, synthetic vectors, drugs, cells, or naturally-occurring or synthetic proteins or other therapeutic agents in a manner that nourishes and sustain production and secretion of the therapeutic agents in vivo.
It would also be desirable to provide methods and apparatus for delivering bioactive agents intravascularly, wherein, once the efficacious agent has dispersed, the delivery system reconfigures to mitigate risk of complication to the patient.